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H. Karsen et al /Herpes simplex

Eastern Journal of Medicine 15 (2010) 34-39 Case Report

Herpes simplex encephalitis

Hasan Karsena, Cengiz Demirb, Mustafa Kasım Karahocagilc *, Mahmut Sünnetcioğluc, Hayrettin Akdenizc

a Department of Infectious Diseases and Clinical Microbiology, Şanlıurfa State Hospital, Şanlıurfa/Turkey b Department of Internal Medicine, Yuzuncu Yil University, Faculty of Medicine, Van/Turkey c Department of Infectious Diseases and Clinical Microbiology, Yüzüncü Yıl University, Faculty of Medicine, Van/Turkey

Abstract. We presented four cases diagnosed with Herpes simplex encephalitis of those treated in our clinic in 2006 one of whom died, one recovered without any sequels. Two cases were left with advanced motor mental sequel. In this paper, clinical and laboratory findings along with diagnosis and treatment of encephalitis were discussed.

Key words: Herpes Simplex virus, encephalitis, diagnosis and treatment

1. Introduction 2. Case reports Case 1: A 21 year-old male patient was Herpes Simplex virus (HSV) is the most admitted to Van State Hospital with complaints important causative agent of endemic focal of fever, , nausea and vomiting, fatigue encephalitis. Sensitivity and specificity of and loss of appetite which developed the detection of HSV-DNA from previous day. The next day he had disorganized (CSF) with polymerase chain reaction (PCR) speech, uncontrolled movements, ravings and method in diagnosis of HSV encephalitis is convulsions, and then he fainted and lost accepted as 98% and 94–100% respectively. consciousness. The patient came to the PCR method is assessed as gold standard method Emergency Department of our hospital with in diagnosis of HSV encephalitis nowadays (1). these complaints. In his physical examination, In untreated or lately treated cases, mortality and the general status was bad, consciousness closed, sequel rates are very high, but early treatment arterial blood pressure 110/80 mmHg, pulse rate can lead to good results. We presented 4 cases 110/min, temperature 40,7 0C, breath rate that were hospitalized, followed and treated in 30/min. He had neck stiffness, but Kernig and our clinic in 2006 as follows. Brudzinski’s signs were negative. On cardiac auscultation, there was a metallic valve sound. Examination of other systems was normal. 40 days earlier, a prosthetic aorta valve had been replaced and a pacemaker settled. He had been using coumadin tb 1x5 mg due to this operation. CT of the brain revealed no pathology. Lumbar *Correspondence: Dr. Mustafa Kasım Karahocagil puncture could not be performed due to his Department of Infectious Diseases and Clinical elevated protrombin time (PT): 61 sec (INR Microbiology value 7.5). After 2 units of fresh frozen plasma Faculty of Medicine, Yüzüncü Yıl University and 1 ampoule vitamin K, PT reduced to 19 sec 65200 Van / Türkiye (INR 1.6) and was done. In CSF Telephone: + 90 432 2164705 examination, there was 50 leukocytes/mm3 (80% Fax: + 90 432 2167519 mononuclear cells), CSF glucose 102 mg/dl Email: [email protected] (simultaneous blood glucose 138 mg/dl), CSF [email protected] protein 283 mg/l (normal: 150–450 mg/l). The patient was hospitalized with a preliminary examinations, count was 14.200/mm3 (with differential of 78%

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H. Karsen et al /Herpes simplex encephalitis

polymorphonuclear leukocytes, 12% monocytes He was considered as herpes encephalitis and 8% ), hemoglobin (Hb) 12.8 based on his clinical and laboratory findings and g/dl, platelets 102.000/mm3, C-RP 243 mg/dl, i.v. acyclovir 3x10 mg/kg/day was started in Brucella Wright Test both in blood and CSF was addition to antiedema and steroid treatment. negative. Gram and Ziehl-Neelsen staining of Phenitoin and oxcarbazepine were added for the CSF did not reveal any organism. In addition his convulsions. Brain MRI did not reveal any to antiedema and steroid treatment, the patient pathology. EEG of the patient could not be was given i.v. acyclovir 3xl0 mg/kg/day with a entirely evaluated because of intubation and lack preliminary diagnosis of herpes encephalitis of compliance. HSV type 1 DNA was measured based on clinical and laboratory findings. EEG as 16.800 copy/ml in the Central Microbiology of the patient could not be assessed because of Laboratory of Yüzüncü Yıl University Medical the pacemaker interference. Brain MRI could not Faculty. Tracheostomy was applied one week be performed due to prosthetic aorta valve. later. Chest tube was settled at the twelfth day HSV-DNA was measured in CSF by PCR because of development of pneumothorax during method (Herpes Simplex I-II PCR Test, Roche his follow up at the Intensive Care Unit. Light Cycler System) in the Central Secondary bacterial which developed Microbiology Laboratory of Yüzüncü Yıl due to Acinetobacter and Pseudomonas spp. University Medical Faculty and was found were treated with appropriate antibiotics. positive (HSV type I DNA: 21.000 copy/ml). Acyclovir treatment was completed to 21 days The consciousness of the patient recovered after and stopped. Pneumothorax and general status of 3 days of treatment and his temperature subsided the patient improved, but he did not come to. at the fourth day of treatment. The patient was The patient was left with advanced motor and discharged with full recovery after two weeks mental sequels. He was referred to a treatment of acyclovir. Rehabilitation Center after one month of his Case 2: Complaints of fever and headache hospitalization. started in a 19 year-old male patient. The next Case 3: Complaints of fever and headache day tonic clonic generalized convulsions started in a 26 year-old male patient. The next developed and he fainted. His temperature was day, he suddenly fainted and came to 10 minutes measured as 40 0C at Van State Hospital. He was later. He was admitted to the Emergency given symptomatic treatment and recovered Department of our hospital with complaint of consciousness 2 hours later. Approximately 7 convulsion and fainted again when he was there. hours later, he experienced tonic clonic Brain CT was evaluated as normal. In generalized convulsion again and was referred to neurological and psychiatric consultations, he the Emergency Department of our hospital. was evaluated as normal and sent to his home. There was no pathology in his brain CT. In The day after, he was referred to a Private lumbar puncture, there was 40 leukocytes/mm3 Hospital and brain MRI taken there revealed (60% mononuclear cells) in the CSF, glucose 67 marked lateral ventricle temporal horns mg/dl (simultaneous blood glucose) 106 mg/dl) especially being apparent in the right side. The protein 370 mg/l (normal: 150–450 mg/l). He EEG taken at the same day showed sharp wave was hospitalized in the Intensive Care Unit with discharges on the temporal region. With these preliminary diagnosis of encephalitis. In his results, he was diagnosed with cephalgia and physical examination, general status was bad, given cefazolin, metamizole sodium, consciousness closed. The patient was intubated oxcarbazepine and chlorpheniramine maleate. He because of irregular and inadequate breathing. used these drugs, but he did not benefit. His Arterial blood pressure was 100/60 mmHg, pulse headache and temperature increased, he began to rate: 120/min, temperature 39 0C, breath rate: speak nonsense and show harmful behaviour to 18/min. In neurological examination, neck himself. He was referred to the Psychiatry stiffness was positive, but Kernig and Clinic; he was trying to insert his hand into the Brudzinski’s signs negative. Examination of doctor’s pocket and take his belongings. The other systems was normal. In laboratory next day, he was referred to the Neurology examinations: WBC was 15.600/mm3 (with Clinic and given one ampoule diazepam, so after differential of 88% polymorphonuclear 5 days of these complaints, he was admitted to leukocytes, 5% lymphocytes, 5 % monocytes), the Emergency Department of our hospital with Hb: 15.4 gr/dl, platelets: 214.000/mm3, C-RP closed consciousness. Brain CT was taken, yet 146 mg/l, Brucella Wright test in the CSF and revealed no pathology. In lumbar puncture, there blood was negative. There was no organism in was 570 leukocytes (80% mononuclear cells), Gram and Ziehl-Neelsen stainings of the CSF. glucose 65 mg/dl (simultaneous blood glucose)

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H. Karsen et al /Herpes simplex encephalitis

Eastern Journal of Medicine 15 (2010) 34-39 Case Report

112 mg/dl), protein 577 mg/l (normal 150–450 encephalitis based on her clinical and laboratory mg/l ). Thus the patient was hospitalized with findings. preliminary diagnosis of encephalitis. In his In her physical examination, general status was physical examination, general status was bad, bad, consciousness confused, arterial blood consciousness closed, arterial blood pressure 160/110 mmHg, pulse rate 110/min, temperature 130/70 mmHg, pulse rate 120/min, temperature 38 0C, breath rate 18/min. Neck stiffness was 39.5 0C, breath rate 22/min. Neck stiffness was positive, Kernig and Brudzinski’s signs were positive, Kernig and Brudzinski’s signs negative. Gram and Ziehl-Neelsen stainings of negative. Examination of other systems was the CSF revealed no organisms. IV acyclovir normal. In laboratory examinations, WBC was 3xl0 mg/kg/day was started to the patient on 16.700/mm3 (with differential of 85% considering herpes encephalitis based on her polymorphonuclear leukocytes, 7% monocytes clinical and laboratory findings in addition to and 6% lymphocytes), Hb 15.7 g/dl, platelets antiedema and steroid treatment. HSV type 1 177.000/mm3, C-RP 31 mg/l, Brucella Wright DNA measured with PCR method revealed Test in the CSF and blood was negative. Gram 95.400 copy/ml in the Central Microbiology and Ziehl-Neelsen stainings of the CSF revealed Laboratory of Yüzüncü Yıl University Medical no organisms. IV acyclovir 3xl0 mg/kg/day was Faculty. EEG taken on the 4th day revealed started to the patient considering Herpes multifocal sharp wave discharges on fronto- Encephalitis based on his clinical and laboratory temporal regions of both hemispheres. findings in addition to antiedema and steroid Additionally focal sharp waves were observed on treatment. HSV type 1 DNA was measured as posterior regions of the right hemisphere. Brain 113.000 copy/ml with PCR method in the MRI taken on the fifth day of her hospitalization Central Microbiology Laboratory of Yüzüncü revealed widespread signal increases on both Yıl University Medical Faculty. The fever hemispheres especially more marked on the left subsided on the 5th day, but reincreased on the temporal region. Existing meningeal contrastings 9th day. His breathing deteriorated and he was after injection of i.v. contrast substance were taken to the Intensive Care Unit. Appropriate evaluated as encephalitis. Brain MRI taken on antibiotics were added because Acinetobacter the 15th day of hospitalization revealed increased and Pseudomonas spp. were grown from blood signal intensities in cortical, subcortical white cultures while he was in the Intensive Care Unit. matter of the left . Additionally Brain CT taken there revealed infarcts in the left there were signal increases on the right frontal hemisphere and pons, pressure to the left anterior lobe, and contrast involvement was ventricle and shift to right from the left. On the observed after i.v. contrast substance injection. 18th day of hospitalization, his fever subsided In comparison of two MRIs, partly regression and acyclovir was completed to 21 days and was observed in lesions on the left temporal lobe stopped. He was left with advanced mental and and the result was evaluated as herpes motor sequels and therefore sent to a encephalitis. In clinical follow-up of the patient, Rehabilitation Center for treatment. fever did not subside, the temperature was Case 4: A 27 year-old female patient had a always 38–38.5 0C. On the 6th day of headache lasting for a week. Then her headache hospitalization, respiratory failure developed, increased and she had also fever. After 3 days of thereupon she was intubated and referred to the complaints, she had difficulty recognizing her Intensive Care Unit. On the 8th day of relatives, began to speak nonsense and the day hospitalization, her blood glucose levels after generalized tonic clonic convulsions increased and insulin was started. On the 9th day, developed two times lasting 2-3 minutes with 5 tracheostomy was opened. On the 11th day, hours apart. She was refereed to a doctor with sinusal tachycardia started (pulse 160/min) and these complaints, but she did not benefit from antiaritmal treatment was added. In ICU, the treatment. After 6 days of her complaints, Pseudomonas spp. and MRSA were grown out of she was admitted to our Emergency Department the tracheostomy materials, and required with confusion. Brain CT of the patient revealed antibiotics were added. On the 30th day, coldness moderate edema in both hemispheres. In lumbar developed on her right leg and pulsations of her puncture, CSF had 380 leukocyetes/mm3 (80% right leg were not able to be felt. Thus mononuclear cells), glucose was 56 mg/dl antithrombolytic treatment was started. On day (simultaneous blood glucose) 97 mg/dl), protein 31, she died due to cardiopulmonary arrest. 564 mg/l (normal 150–450 mg/l). The patient Clinical and laboratory findings of the cases are was hospitalized with a preliminary diagnosis of shown in tables 1-2.

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H. Karsen et al /Herpes simplex encephalitis

Table 1. Clinical findings of the cases

Case 1 2 3 4 Age - Gender 21- Male 19 - Male 26 - Male 27 - Female Symptoms Fever, headache, Fever, headache, Fever, headache, Fever, headache, nausea, vomiting, Tonic-clonic nonsense speech, nonsense speech, faintness, coma generalized faintness, proposagnosia, * convulsion, coma convulsion, coma convulsion, coma Temparature 40.7 ˚C 40 ˚C 39.5 ˚C 38 ˚C consciousness Closed Closed Closed Closed At Admission Signs of Neck stiffness + Neck stiffness + Neck stiffness + Neck stiffness + Meningeal Kernig sign – Kernig sign – Kernig sign – Kernig sign – Irritation Brudzinski – Brudzinski – Brudzinski – Brudzinski – EEG Not performed Normal Sharp wave Bilateral multifocal due to metal heart discharges sharp wave valve discharges CT Normal Normal Normal Slight edema MR Not performed Normal Marked ventricle Signal increase in due to prosthetic horns both hemispheres, valve contrast involvement in meninges Lasted 3 days 3 days 5 days 6 days duration when treatment was started Outcome Recovery Refereed to a Refereed to a Exitus rehabilitation center rehabilitation center due to sequels due to sequels *Proposagnosia: Difficulty recognising faces

Table 2. Laboratory findings of the cases

Cases 1 2 3 4 CSF Leukocyte 50 (80% MNL) 40 (60% MNL) 570 (80% MNL) 380 (80% MNL) Count/mm3 CSF Protein 283 mg/L 370 mg/L 577 mg/L 564 mg/L CSF Glucose/ 102/138 67/106 65/112 56/97 Blood Glucose CSF HSV-DNA 21.000 copies/ml 16.800 copies/ml 113.000 copies/ml 95.400 copies/ml WBC count 14.200 15.600 16.700 9.500 (78% PNL) (88% PNL) (75% PNL) (3% PNL) MNL: Mononuclear leukocytes. PNL: Polymorphonuclear leukocytes

3. Discussion and a lifelong carriage begins. 70–90% of adults possess antibodies to HSV–1 (2). Herpes simplex virus has a worldwide Herpes encephalitis is the most frequent type distribution. Humans appear to be the only of all encephalitides and the one with the highest natural reservoir. Primary infections occur in the mortality rate. Its annual estimated incidence is first years of life parallel to the disappearance of about 2–3 cases in one million persons. 95% of the antibodies acquired from the mother. cases of herpes encephalitis is caused by HSV Although specific antibodies develop after subtype 1. It enters into the body through the recovery, virus does not leave the human body oropharyngeal mucosa, conjunctiva and damages

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H. Karsen et al /Herpes simplex encephalitis

Eastern Journal of Medicine 15 (2010) 34-39 Case Report skin. It remains latently in the neurons and the detection of HSV-DNA is the same as the causes recurrent infections. Antibodies temporal lobe biopsy. In the same study, it has developed against the virus exist in 90% of been shown that antiviral therapy has very little humans, but how the virus is activated to cause effect on the sensitivity and specificity of the In the clinical picture of encephalitis, there is a detection of HSV-DNA in the CSF with PCR. prodromal period consisting of fever and Although HSV-DNA is found positive in all headache which lasts 2-3 day. Then psychotic samples taken before treatment and in 98% of the behaviour abnormalities, epileptic , samples taken one week after treatment, it has hemiplegia, speech disorders, amnesia, stupor been found positive in 49% and only in 21% of the and coma may develop (2-4). All of our cases samples taken in the second week and 15 days and had fever and headache and then faintness and over after treatment respectively (7). HSV-DNA epileptic seizures developed and eventually the was positive in all our cases from the first day of clinical picture deteriorated with the the disease. It is not known whether the high titers development of coma. Thus, HSV encephalitis of HSV-DNA are associated with the prognosis or should be taken into consideration in variety of not (5). There was no such relation in our cases diagnosis of all patients with fever, headache too. Because HSV-DNA could not be measured in and altered consciousness. HSV is a all laboratories and the duration between the neuronophagic virus which characteristically transfer of the CSF to an advanced center and the causes focal hemorrhagic in temporal obtaining of the result can affect negatively on lobe. This property is accepted as a distinctive morbidity, treatment should be started finding in the differential diagnosis from other immediately in patients whose symptoms are encephalitides (5). But this finding was not consistent with HSV encephalitis. Although present in all our cases, therefore temporal lobe leukopenia and predominance of mononuclear pathology should not be always sought in HSV leukocytes are generally expected in . A case beginning with talamic infections; on the contrary there was leukocytosis involvement has been reported in the literature and predominance of polymorphonuclear (6). While pathological signs can be leukocytes in all our cases. Therefore, when the established only at the fifth day in the brain patient was evaluated, this should be taken into CT, these signs can be established at the account. Cell count in the CSF was between 40– second day in the MRI. In our cases, only in 470/mm3. CSF glucose was in normal limits in all case 4, there was a slight edema in brain CT our cases. CSF protein was normal in the first two because it was taken after 5 days of the disease cases, and slightly elevated in the last two cases. onset. MRI could not be performed in case 1 In herpes encephalitis, it has been stressed on the because of the existing pacemaker. In case 2, evidence of erythrocytes in the CSF (500/mm3) in MRI was taken after 3 days, but no pathology the lumbar puncture (8). But there was no red was observed. In cases 3 and 4, MRI taken at blood cell in the CSF of neither of our cases. the second and sixth days of the disease Akvan Oğuz et al. (9) have reported two cases respectively revealed miscellaneous with entirely normal CSF findings which were pathologies above mentioned. Consequently diagnosed with HSV encephalitis by means of when pathology does not exist in brain MRI HSV-DNA detection. Thus when evaluating the taken at the second day or after, HSV CSF findings, one should not make a mistaken encephalitis should not be ruled out. In the last diagnosis and delay the treatment taking into ten years, the diagnosis of HSV encephalitis account this finding. While the mortality rate is had been tried to be made by temporal lobe 70% in untreated cases, success rate may increase biopsy or cultural methods or histochemical to 92% when treatment is started early (2). Of our analyses which are difficult methods to apply cases, the patient in whom treatment was started and quite invasive. Nowadays, detection of on day 6 died and two patients in whom treatment HSV-DNA in the CSF with PCR method has was started on days 3 and 5 were left with been the gold standard for the diagnosis of advanced irreversible mental-motor sequels, and HSV encephalitis. HSV-DNA in the CSF can they were sent to an advanced center for be found positive from 24 hours on after the rehabilitation. In the patient who recovered, initiation of disease symptoms to one week treatment had been started on day 3. That is, our later after the beginning of the treatment. The overall success rate was 25%. This was attributed sensitivity and specificity of the detection of to the delay in diagnosis because they were HSV-DNA has been found to be 98% and 94– referred to us at least 3 days after the disease 100% respectively in the studies performed (7). onset. Acyclovir is accepted to be the most It has been shown that the diagnostic value of efficient therapeutic agent and it is reported that

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H. Karsen et al /Herpes simplex encephalitis

addition of steroid to treatment is useful References (10,11). In the studies performed, while the mortality rate is reported as 50-55% in patients 1. Eren SS, Öztoprak N, Çevik MA, et al. Herpes treated with vidarabine, it has been found 20- simplex ensefaliti: Bir olgu sunumu. Flora Derg 2005; 30% in patients treated with acyclovir (12). 10: 148-150. Intravenous use of acyclovir at a dose of 3x10 2. Mutluer N. Ensefalomyelitler ve Nöritler, Topçu AW, Söyletir G, Doğanay M (eds.) İnfeksiyon Hastalıkları mg/kg/day for 21 days is accepted to be the ve Mikrobiyolojisi. 2nd ed. Nobel Tıp Kitapevleri, most appropriate choice in treatment of herpes İstanbul 2002: 1019-1023. encephalitis (13, 14). The same treatment 3. Fleming DT, McQuillan GM, Johnson RE, et al. modality was used in all our patients. Although Herpes simplex virus type 2 in the United States, 1976 brain CT of case 3 taken on day 5 of the to 1994. NEJM 1997; 337: 1105-1111. disease was normal, the CT taken on day 10 of 4. Schlitt M, Lakeman FD, Whitley RJ. and herpes simplex encephalitis. South Med J 1985; 78: the disease (day 5 of hospitalization) revealed 1347-1350. infarcts on the left hemisphere and pons, 5. Whitley RJ, Soong SJ, Linneman C Jr, et al. Herpex pressure to the left ventricle, and shift to the simplex encephalitis clinical assessment. JAMA 1982 right side from the left. Also while our case 4 ; 247 : 317-320. was conscious on admission and although 6. Sakaguchi J, Yonemura K, Hashimoto Y, Hirano T, treatment was started immediately, her Uchino M. [Herpes simplex encephalitis originating from bilateral thalamic lesions with hemorrhagic consciousness gradually closed in a couple of component]. Rinsho Shinkeigaku 2005; 45: 368-371. days and eventually died. Treatment was 7. Lakemman FD, Whitley RJ. Diagnosis of herpes started 3 days after the beginning of the disease simplex encephalitis: Application of polymerase chain symptoms in our case 2, but the clinical picture reaction to cerebrospinal fluid from brain-biopsied did not improve and on the contrary advanced patients and corelation with disease. J Infect Dis 1995; 171: 857-863. mental-motor sequels developed. In all these 8. Durmaz Çetin B, Hamsan H. Herpes Ensefalitleri. three patients, although treatment was started Klimik Derg 2004; 17: 68-71. early within hours of hospitalization on 9. Avkan Oguz V, Yapar N, Sezak N, et al. Two cases of considering herpes encephalitis, the fact that herpes encephalitis with normal cerebrospinal fluid one of whom died and two of whom developed findings. Mikrobiyol Bul 2006; 40: 93-98. advanced mental-motor sequels made us 10. Sköldenberg B, Forsgren M, Alestig K, et al. Acyclovir versus vidarabine in herpes simplex consider that whether acyclovir alone is always encephalitis: Randomised multicenter study in adequate in the treatment of herpes encephalitis consecutive Swedish patients. Lancet 1984; 2: 707- or not. In some studies, in severe cases of 711. herpes encephalitis and in cases not responded 11. Shoji H. Japanese guidelines for the management of to acyclovir alone, the combination of herpes simplex encephalitis; comparison with those from the International Management Herpes Forum. acyclovir and other antiviral agents (vidarabine Rinsho Shinkeigaku 2006; 46: 955-957. and beta-interferon) has been used together and 12. Whitley RJ, Alford CA, Hirsch MS, et al. Vidarabine it has been obtained good results (6, 15, 16). versus acyclovir therapy in herpes simplex We also wanted to use combination of encephalitis. N Engl J Med 1986; 314: 144-149. acyclovir and vidarabine in our patients. 13. Dorsky DI, Crumpacker CS. Drugs five years later: However, since we could get no positive result Acyclovir. Ann Intern Med 1987; 107: 859-874. from the researches and attempts we made both 14. Alp E, Yıldız O, Gökahmetoğlu S, et al. Herpes ensefalitinin erken tanısında moleküler ve in the country and abroad, we were forced to görüntüleme yöntemlerinin önemi: bir olgu sunumu. suffice with acyclovir. In conclusion, for early Flora Derg 2005; 10: 145-147. diagnosis, detection of HSV-DNA in the CSF 15. Ito S, Hirose Y, Mokuno K. The clinical usefulness of with PCR has been accepted as the gold MRI diffusion weighted images in herpes simplex standard method. encephalitis-like cases. Rinsho Shinkeigaku 1999; 39: 1067-1070. Therefore the most important analysis in 16. Wintergerst U, Belohradsky BH. Acyclovir patients whose symptoms are consistent with monotherapy versus acyclovir plus beta-interferon in herpes encephalitis is the detection of HSV- focal viral encephalitis in children. 1992; DNA in the CSF with PCR. 20: 207-212. The primary drug to be preferred in the treatment is acyclovir, however, especially in irresponsive and severe cases it could be benefited from other antiviral agents.

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